title: Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus.
abstract: Described herein is a general approach to identify novel compounds using the biodiversity of a megadiverse group of animals; specifically, the phylogenetic lineage of the venomous gastropods that belong to the genus Conus ("cone snails"). Cone snail biodiversity was exploited to identify three new mu-conotoxins, BuIIIA, BuIIIB and BuIIIC, encoded by the fish-hunting species Conus bullatus. BuIIIA, BuIIIB and BuIIIC are strikingly divergent in their amino acid composition compared to previous mu-conotoxins known to target the voltage-gated Na channel skeletal muscle subtype Na(v)1.4. Our preliminary results indicate that BuIIIB and BuIIIC are potent inhibitors of Na(v)1.4 (average block approximately 96%, at a 1muM concentration of peptide), displaying a very slow off-rate not seen in previously characterized mu-conotoxins that block Na(v)1.4. In addition, the three new C. bullatus mu-conopeptides help to define a new branch of the M-superfamily of conotoxins, namely M-5. The exogene strategy used to discover these Na channel-inhibiting peptides was based on both understanding the phylogeny of Conus, as well as the molecular genetics of venom mu-conotoxin peptides previously shown to generally target voltage-gated Na channels. The discovery of BuIIIA, BuIIIB and BuIIIC Na channel blockers expands the diversity of ligands useful in determining the structure-activity relationship of voltage-gated sodium channels.
authors.affiliation: Department of Biology, University of Utah, 257 S. 1400 E. Rm. 114, Salt Lake City, UT 84112, USA. holford@biology.utah.edu
authors.forename: Mandë
authors.initials: M
authors.lastname: Holford
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Zhang
authors.forename: K Hanumae
authors.initials: KH
authors.lastname: Gowd
authors.forename: Layla
authors.initials: L
authors.lastname: Azam
authors.forename: Brad R
authors.initials: BR
authors.lastname: Green
authors.forename: Maren
authors.initials: M
authors.lastname: Watkins
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Ownby
authors.forename: Doju
authors.initials: D
authors.lastname: Yoshikami
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.forename: Baldomero M
authors.initials: BM
authors.lastname: Olivera
mesh_terms: D051046:Amino-Acid N-Acetyltransferase; D000818:Animals; D001483:Base Sequence; D044822:Biodiversity; D003001:Cloning, Molecular; D020916:Conotoxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D052078:Conus Snail / Q000235:genetics* / Q000502:physiology*; D018076:DNA, Complementary; D008978:Mollusk Venoms / Q000737:chemistry; D009865:Oocytes; D010802:Phylogeny; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D014981:Xenopus
chemical_list: D020916:Conotoxins; D018076:DNA, Complementary; D008978:Mollusk Venoms; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D051046:Amino-Acid N-Acetyltransferase